Investigations are directed at understanding (1) the mechanism of chloroquine resistance in Plasmodium falciparum, (2) the expression and variation of a gene family (var) that modulates the antigenic and adhesive character of parasitized red blood cells, (3) certain genes that determine invasion pathways by which malaria parasites invade red blood cells, and (4) a defect in parasite gametogenesis that has been mapped to chromosome 12. A determinant of chloroquine resistance has been localized to a <50 kb segment of the parasite's 7th chromosome. Transcribed genes and DNA sequence data from this segment are being obtained to identify the determinant and the mechanism of resistance. Factors responsible for the spread of drug resistance are being examined in epidemiological studies in Mali. Antigenic variation and cytoadherence of parasitized red blood cells is mediated by a large diverse, family of genes (var) that have a copy number of 50-150 per parasite. The var family in turn belongs to a superfamily that also includes genes of red cell invasion (eba-175, ebl-1, DABP genes). Expression and trafficking of the var gene products to the erythrocyte surface is under investigation. An unusual pool of sterile RNA transcripts (gfh) may be involved in var gene rearrangements or expression. A defect in the development of P. falciparum male gametes has been traced to a spontaneous mutation in a cultivated parasite line. The mutation has been localized to an 800 kb segment of chromosome 12. Transfection of parasite erythrocytic stages is now established. Chloramphenicol-acetyl transferase and luciferase have been expressed in intraerythrocytic P. falciparum parasites, and homologous integration of pyrimethamine-resistance genes into targeted regions of parasite chromosomes has been achieved.